NO125142B - - Google Patents

Description

Analogy method for the production of

new, therapeutically active cyclopeptides.

The invention relates to an analogue method for the production of new, therapeutically active cyclopeptides with the general formula

R' - cyclopeptide A (I)

where - cyclopeptide A means a nonapeptide residue with the formula

in which

L MePro stands for: L 4-transmethylpropyne

L MeThr denotes: L N-methylthreonine

L MeVal stands for: L N-methylvaline

D MeLeu stands for: D N-methylleucine

L Pro denotes: L proline

Gly stands for: glycocol

L Leu denotes: L leucxn

L Thr stands for: L threonine

R<1> denotes an alkanoyl, alkenoyl, alkadienoyl, alkyloxycarbonyl, aralkanoyl, aroyl, arylsulfenyl, arylsulfonyl, cycloalkylcarbonyl, heterocyclylcarbonyl or heterocyclylalkanoyl group or a residue of a linear peptide group connected through a carbonyl group with the nitrogen atom in the L-4-transmethyl-proline in the side chain of cyclopeptide A; the alkyl parts in the alkanoyl groups being straight or branched chains containing 1-17 carbon atoms, optionally substituted with one or more halogen atoms, amino groups or methylthio groups; in that the alkenyl parts of the alkenoyl groups contain 10 carbon atoms; wherein the alkadienyl parts of the alkadienoyl groups contain 5 carbon atoms; wherein the alkyl parts of the heterocyclylalkanoy groups are straight or branched chains, containing 2-10 carbon atoms; wherein the alkyl parts in the alkyloxycarbonyl groups contain 9-11 carbon atoms and are optionally substituted with a diethylamino group; in that the alkyl parts in the aralkanoyl groups contain 1 or 2 carbon atoms and are optionally substituted with an amino group; wherein the aromatic parts in the aralkanoyl, aroyl, arylsulfenyl, or arylsulfonyl groups are made up of a benzene or naphthalene nucleus which is optionally substituted with a methyl, hydroxyl, dimethylamino, acetylamino, nitro, benzoyl or diethylamino group; wherein the heterocyclic parts in the heterocyclylcarbonyl or heterocyclylalkanoyl groups constitute 5~ or 6-membered mononuclear heterocycles containing nitrogen or a phenotiazinyl group, which may be substituted with one or more methyl or nitro groups; wherein the cycloalkyl part in the cycloalkyl-carbonyl groups constitutes a cyclohexyl group substituted with an amino group; since the remains of the linear peptide groups contain 2-3 amino acids of series L; and since the amino groups which constitute substituents on the alkyl or cycloalkyl parts in the groups defined above, as well as the amino group in the linear peptide groups may optionally be substituted with one or more straight-line or branched alkyl groups, containing 1-14 carbon atoms, alkanoyl groups containing 2-18 carbon atoms, tert-butyloxycarbonyl, benzyl or benzyloxycarbonyl groups; in the form of bases, addition salts with acids and quaternary ammonium salts, the method being characterized by a) condensing H-cyclopeptide A with an acid with the general formula R'OH, where R' denotes an alkanoyl, alkenoyl, alkadienoyl , aralkanoyl, aroyl, cycloalkylcarbonyl, heterocyclylcarbonyl or heterocyclylalkanoyl group or a residue of a linear peptide group, these various groups having the above definitions, and the amino groups present being substituted as indicated above, or with an activated derivative of this acid as azide, an activated ester or acid anhydride or an acid chloride, or b) when R' denotes an alkyloxycarbonyl group which is optionally substituted in the above-mentioned manner, an alkyl chloroformate which is optionally substituted in the above-mentioned manner is reacted with H-cyclopeptide A, or c) when R' denotes an arylsulfonyl or arylsulfonyl group, a compound of the general formula is reacted where R"^ is a benzene or naphthalene nucleus which is optionally substituted as mentioned above, and n is 0 or 2, with H-cyclopeptide A, after which a compound thus formed is optionally converted with formula

where -cyclopeptide A has the above meaning, and R,, -and R^ which may be the same or different, denote a hydrogen atom or an alkyl group, containing 1-5 carbon atoms, to another compound-

Else of formula (I) by reaction with an acid of the general formula R'OH, where R' denotes -an alkanoyl group, containing 2-18 carbon atoms or a linear peptide residue, containing 1-2 amino acids, whose amino groups can be substituted on the above way, or with an activated derivative of this acid such as an azide, an activated ester, an acid anhydride or an acid chloride, after which the amino groups substituted by tert, butyloxycarbonyl, benzyl or benzyloxycarbonyl groups and converts the formed base into a salt or vice versa..

The cyclopeptide A itself (where R' is replaced by a hydrogen atom) can be obtained by careful hydrolysis of the antibiotic 11072 R.P. whose manufacture is described in the Norwegian patent no. 116,283. It has then been determined that this antibiotic has the probable structure:

The antibiotic 11,072 R.P. can be hydrolyzed to cyclopeptide A by means of an inorganic or organic acid in solution in an organic solvent. Preferably, anhydrous methanolic hydrogen chloride is used. The reaction is carried out at a temperature close to 20°C and it is complete after approx. two hours.

As condensation methods there is reason to mention, for example, the methods that use a carbodiimide such as dicyclohexylcarbodiimide, the method with azide, the method with activated esters, the method with mixed anhydride and the method with acid chlorides.

By these methods, the functionals are free groups

which should not participate in the reaction, advantageously protected by groups that can later be eliminated without affecting the rest of the molecule. Residues that can be eliminated by hydrolysis or reduction are usually used. The amino groups are preferably protected by means of alkoxycarbonyl groups such as tertiobutyloxycarbonyl, aralkyloxycarbonyls such as benzyloxycarbonyl or aralkyl, such as benzyl.

Especially if you use an acid with the general formula

wherein R" has the same definition as R<1>, but cannot denote an alkoxycarbonyl, arylsulphenyl or arylsulphonyl radical, the reaction is carried out in an organic solvent such as ethyl acetate, dimethylformamide, acetonitrile or methylene chloride at a temperature between 0 and 30°C in the presence of a carbodiimide such as dicyclohexylcarbodiimide.

If one uses an azide with the general formula in which R" has the above meaning, the reaction is carried out in an organic solvent such as ethyl acetate, optionally in the presence of an organic base such as triethylamine and at a temperature between -15 and +25°C.

The azides of the general formula V are usually prepared by reacting an alkali metal nitrite with a corresponding hydrazide in an acidic environment.

If one uses an activated ester with the general formula:

wherein R" has the meaning given above, and X denotes a residue of phenol or of N-hydroxylated nitrogen heterocycle, which activates the carbonyl group to which it is bound as N-hydroxysuccinimide, p-nitrophenol, 2, U,5-trichlorophenol or 1- hydroxy-piperidine, the reaction is carried out in an organic solvent such as ethyl acetate or dimethylformamide in the presence of a carbodiimide such as dicyclohexylcarbodiimide at a temperature between -15 and +25° C. in the presence of an organic base such as triethylamine if necessary. The activated esters are usually prepared in situ according to common methods.

If one uses an acid anhydride with the general formula:

wherein R" has the above meaning and R-|_ denotes an alkyl radical containing 1-5 carbon atoms, the reaction is carried out in an organic solvent such as methylene chloride at a temperature between -15 and +20°C, possibly in the presence of an organic base which triethylamine.

Mixed anhydrides with. the general formula VII is usually prepared in situ by reacting an alkyl chloroformate such as ethyl or isobutyl chloroformate with an acid with the general formula IV in an organic solvent such as methylene chloride in the presence of an organic base such as triethylamine and at a temperature close to -1-0° C.

If one uses an acid chloride with the general formula:

in which

R" has the above meaning, the reaction is carried out in an organic solvent such as methylene chloride, possibly in the presence of an organic base such as triethylamine, and at a temperature between

-15 and +25°C

When R' denotes an above-defined, optionally substituted, , , , , , , , , cyclopeptide A is reacted with a chloroformate of the general formula:

in which

R"' denotes an alkyl radical, containing 1-15 carbon atoms, optionally substituted with a dialkyl radical, where each alkyl part contains 1-5 carbon atoms in an organic solvent such as methylene chloride, in the presence of an organic base such as triethylamine and at a temperature between -15 and +30°C.

If R' denotes an above-defined aryllauphenyl, arylsulfinyl or arylsulfonyl radical, the cyclopeptide A is reacted with a compound of the general formula:

in which

IV

R is a benzene or naphthalene ring, which is optionally substituted with one or more alkyl radicals, amino-dialkylamino, alkanoylamino or nitro groups,

and n denotes 0 or 2 in an organic solvent such as ethyl acetate or methylene chloride in the presence of an organic base - such as triethylamine - and at a temperature between -15 and +20°C.

When in the above-mentioned methods the radicals R", R"' and RIV in the compounds IV, V, VI, VII, VIII, IX or X contain protective groups, these protective groups are then eliminated using common methods such as catalytic hydrogenation or acid hydrolysis.

The new products of the general formula I can optionally be purified by means of physical methods (such as chromatography) or chemical methods (such as formation of salts soluble in water, filtration and lyophilization of the solutions formed, then cleavage of the products formed).

According to the invention, the new products can be converted into addition salts with acids or into quaternary ammonium salts, depending on the nature of the substituent -R<*.>

The addition salts can be obtained by reacting the new compounds with acids in a suitable solvent. Usually, the base is dissolved in water by adding the theoretical amount of acid and the resulting solution is lyophilized.

rThe quaternary ammonium salts can be obtained by reacting the new compounds with esters, possibly in an organic solvent at normal temperature or more quickly by mild heating.

The new products, as well as - their addition salts

and their quaternary ammonium salts, have interesting properties for therapeutic use. They are antibiotic agents that have a strong anti-tuberculosis effect and d-essuten a good effect against gram-positive and gram-negative organisms.

They have given good results in anti-tuberculosis activity tests in vitro and in vivo. They have inhibited the growth of virulent tubercle bacilli (human strains such as H^yRv., bovine strains and various resistant mutants thereof). .The activity in vitro was determined using the dilution method in Dubos' medium. Under these conditions, the minimal inhibitory concentration is between 0.005 and 1 µg/ml.

Of particular interest are the compounds of the general formula I, in which R' denotes an alkanoyl or alkenoyl radical which is optionally substituted with an amino group or an alkylthio radical or a linear peptide radical, the amino groups may be substituted as indicated above.

The activity in vivo is determined on mice infected experimentally and subjected to treatment for three weeks starting from the day of infection. Untreated mice die after a period of 20-30 days. Under these conditions, the minimum effective doses can be determined; they are between 50 and 300 mg/kg per os.

Of particular interest are the compounds of the general formula I, in which R' denotes an alkanoyl radical which is substituted with an amino group or a linear peptide group, the amino groups may be substituted as indicated above.

For medical use, the new compounds are used either in the form of bases or in the form of addition salts or quaternary ammonium salts which are pharmaceutically acceptable, i.e. non-toxic at the doses used.

Examples of pharmaceutically acceptable addition salts include salts of inorganic acids (such as hydrochlorides, sulphates, nitrates, phosphates) or of organic acids (such as acetates, propionates, succinates, benzoates, fumarates, maleates, tartrates, methanesulfonates, benzenesulfonates, theophylline acetates, salicylates, phenol phthalinates, methyl bis-g-oxy-naphthoates or substitution derivatives of these acids.

Examples of pharmaceutically acceptable quaternary ammonium salts include derivatives of inorganic or organic esters, such as chloro, bromo or iodomethylates, ethylates, allylates or benzylates, methyl or ethyl sulfates, methanesulfonates, benzenesulfonates or substitution derivatives of these connections.

The following examples show how the invention can be carried out in practice.

The Rf values for the products are determined by means of thin-layer chromatography on silica gel.

Example 1. (preparation of cyclopeptide A).

150 g of antibiotic peptide, which has been obtained as described in the Norwegian patent no. II6.283, dissolve in 1320 ml of 4.5 N hydrochloric acid methanol. The mixture is stirred for 2 hours at 20°C and then concentrated to dryness under reduced pressure (25 mm Hg). The residue is extracted twice with 250 ml of methanol each time. On evaporation, these methanol extracts give an amorphous residue which is dissolved in a mixture of chloroform-methanol (95=5 parts by volume). The resulting solution is poured through a column with a diameter of 11 cm and containing 2 kg of silica gel. The elution is carried out using the same solvent.

* U 'I «

Fractions of 640 ml are collected. Fractions 10 - 16 make it possible to obtain 123.3 g of cyclopeptide A, which is chromatographically pure in a yield of 95.5%.

Rf = 0.55 (silica gel; 1,2-dichloroethane-methanol, 65 - 35 parts by volume)

Z"a_7p<2> = -62° (c = 0.5, methanol).

Example 2.

3.35 g of cyclopeptide A are dissolved in 70 ml of ethyl acetate. 1.13 g of N a -acetyl-N- £, -benz<y>lox<y>carbonyl-L-lysine are added. It is cooled in an ice bath and 0.8 g of dicyclohexylcarbodiimide is added. The mixture is stirred for two hours under external cooling using an ice bath and then overnight at 20°C. Five drops of glacial acetic acid are added and then filtered from insoluble material formed. The precipitate is washed with ethyl acetate, the organic phases are combined and then concentrated to dryness under reduced pressure (25 mm Hg). The residue is dissolved with 10 ml of ethyl acetate - and the resulting solution is washed successively with a 2% solution of sodium bicarbonate and then with N hydrochloric acid and finally with distilled water. The organic phase is dried over anhydrous sodium sulfate and then filtered. The filtrate is concentrated to dryness under reduced pressure (25 mm Hg).

The impure residue (3.14 g) is placed in a column with a diameter of 3 µm containing 75 g of silica gel. One elutes successively with benzene, the mixtures benzene-ethyl acetate 9 : 1 (parts by volume) and 5 : 5 (parts by volume), ethyl acetate and the mixtures ethyl acetate-methanol 95 : 5 (parts by volume), 90 • 10 (parts by volume) and 75 : 25 (parts by volume) . The fractions eluted with ethyl acetate and with the mixtures ethyl acetate-methanol 95 x 5 and 90 : 10 are combined and concentrated to dryness under reduced pressure (25 mm Hg).

One thus obtains 2.13 g of (N α-acetyl-N--^-benzyloxycarbonyl-L-lysyl)-cyclopeptide A with a yield of 48.5 f°-

N % = 12.43 (theoretical 12.20)

Z~a_7D° = -67.6° (c = 0.5, methanol)

Rf = 0.73 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume).

By working in the same way, starting from suitable starting materials, one produces:

(N-benzyl-N-methyl-L-valyl)-cyclopeptide Å

C % = 64.13 (theoretical 64.30) H %- 8.53 (theoretical 8.67) Rf — 0.67 (silica gel, 1,2-dichloroethane-methanol, 8 : 2 vol-

parts),

the hydrochloride of (N-benzyl-N-methyl-D-valyl)-cyclopeptide A

N % = 11.50 (theoretical 11.69) Cl % = 2.95 (theoretical 2.96) Rf = 0.87 (silica gel, 1,2-dichloroethane-methanol, 65 : 35 parts by volume),

the methanesulfonate of (N-benzyl-N-methyl-DL-valyl)-cyclopeptide A

N % = 10.59 (theoretical 11.13) S % = 2.65 (theoretical 2.55) Rf = 0.74 (silica gel, 1,2-dichloroethane-methanol, 80 : 20 parts by volume), (N-benzyloxycarbonyl -L-valyl)-cyclopeptide A

N % = 11.93 (theoretical 11.76)

Z~<a>_7p° <=> -73.2°" (c - 0.5, methanol)

Rf ~ 0.85 (silica gel, 1,2-dichloroethane-methanol, 65 : 35 parts by volume),

(N-benzyloxycarbonylglycyl)-cyclopeptide A

N fo = 11.87 (theoretical 12.18)

Rf = 0.40 (silica gel, 1,2-dichloroethane-methanol, 88 : 12 parts by volume),

the methanesulfonate of ("N-benzylsarcosyl)-cyclopeptide A

N % = 10.81 (theoretical 11.52) S % = 2.89 (theoretical 2.64) Rf = 0.77 (silica gel, 1,2-dichloroethane-methanol, 65 : 35 parts by volume) T

(N-decanoyl-L-valyl)-cyclopeptide A

N % = 11.60 (theoretical 11.56)

Rf = 0.83 (silica gel, 1,2-dichloroethane-methanol, : 2 parts by volume),

(undecene-10-oyl)-cyclopeptide A

C % = 64.33 (theoretical 64.08) N % = 10.95 (theoretical 11.21) Rf = 0.58 (silica gel, 1,2-dichloroethane-methanol, 8 : 2 parts by volume),

(1-methyl-4-nitro-2-pyrrolylcarbonyl)-cyclopeptide A

N % = 13.8l (theoretical 13.87)

Rf = 0.84 (silica gel, 1,2-dichloroethane-methanol, 8 : 2 parts by volume the hydrochloride of (N-benzyl-N-methyl-L-methionyl)-cyclopeptide A

N % 11.62 (theoretical 11.39) S % = 3.12 (theoretical 2.6l) Rf 0.65 silica gel, n-butanol-acetic acid-water, 4 : 1 : 5

volume fractions),

(N-benzyloxycarbonyl-L-phenylglycyl)-cyclopeptide A

N% ** 11.11 (theoretical 11.42)

Rf = 0.85 (silica gel; 1,2-dichloroethane-methanol, 65 : 35 parts by volume),

the hydrochloride of (N-hexyl-N-methyl-L-valyl)-cyclopeptide A

C % (for the base) = 63.45 (theoretical 63.40),

H % (for the base) = 9.12 (theoretical 9.24)

N % (for the base) = 12.03 (theoretical 12.12),

Rf = 0.53 (silica gel, 1-,2-dichloroethane-methanol, 8:2 parts by volume),

the hydrochloride of (N-benzyl-N-methyl-L-alanyl)-cyclopeptide A

N % = 12.20 (theoretical 11.98) d % = 3.3 {theoretical 3.03) Rf = 0.85 (silica gel, 1,2-dichloroethane-methanol, 65 : 35 parts by volume),

. (N-benzyl-N-methyl-L-phenylalanyl)-cyclopeptide A

N % = 11.50 (theoretical 11.58). Rf = 0.77 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume),

palmitoyl cyclopeptide A

C fo = 64.45 (theoretical 65.24) H $ 9.41 (theoretical 9.51) N fo = 10.30 (theoretical 10.53)

Rf = 0.77 (silica gel, 1,2-dichloroethane-methane, 8 : 2 parts by volume)' ,

undecanoyl cyclopeptide A

C% = 64.78 (theoretical 64.0), H # « 9.28' (theoretical 9.21) N %' = 10.9 (theoretical 11.18)

Rf 0.52 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume) , '

dodecanoyl cyclopeptide A

N % = 11.1 -{theoretical 11.05)

Rf = 0.78 {silica gel, 1,2-dichloroethane-methanol, -8 1 2 parts by volume) ,

£~ L{+) 6-Methyl-Octanoyl7-Eyclopeptide A

G $ » 63.63 {theoretical 63.41) H % = 8.50 (theoretical 9.03) N % = 11.12 (theoretical 11.47),

Rf = 0.77 (silica gel, 1,2-dichloroethane-methanol, 8 : 2 parts by volume), benzoyl cyclopeptide A N % = 11.88 (theoretical 11.86)

Rf 0.85 (silica gel, 1,2-dichloroethane-methanol, 65 : 35 parts by volume),

isonicotinoyl cyclopeptide A

N fo = 13.14 (theoretical 13.17)

Rf =0.83 (silica gel, 1,2-dichloroethane-methanol, 65 : 35 parts by volume),

salicyloyl cyclopeptide A

N % = 11.97 (theoretical 11.68)

Rf = 0.80 (silica gel, 1,2-dichloroethane-methanol, 65 : 35 parts by volume),

decanoyl cyclopeptide A

C % = 63.98 (theoretical 63.69) H % 9.41 (theoretical 9.15) Rf = 0.70 (silica gel, 1,2-dichloroethane-methanol, 65 : 35 parts by volume),

the hydrochloride of (N-hexyl-L-valyl)-cyclopeptide A

N % (for the base) = 12.25 (theoretical 12.27)

Rf = 0.37 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume),

(N-benzyl-N-methyl-L-leucyl)-cyclopeptide A

N % = 11.99 (theoretical 11.91)

Rf = 0.72 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume),

(p-4-methoxybenzyloxycarbonylamino-cyclohexylcarbonyl)-cyclopeptide A

N % 10.8 (theoretical 11.22)

Rf = 0.76-(silica gel, 1,2-dichloroethane-methanol, 8 : 2 parts by volume),

£~{10-methyl-3-phenthiazinyl)-acetyl_7-cyclopeptide A

N % = 11.3 (theoretical 11.56) S % = 2.53 (theoretical 2.64) Rf = 0.56 (silica gel, 1,2-dichloroethane-methanol, 8:' 2 parts by volume) ,

£~2-(3-benzoyl-phenyl)-propionyl7-cyclopeptide A

N % = 10.45 (theoretical 10.55)

Rf = 0.57 (silica gel, 1,2-dichloroeth-methanol, 8:2 parts by volume),

(N,N-diheptylglycyl)-cyclopeptide A

N" % = 11.43 (theoretical 11.56)

Rf = 0.74 (silica gel, 1,2-dichloroethane-methanol, 8 : 2 parts by volume)^

Example 3.

0.21 g of N-tertiobutyloxycarbonyl-L-valine is dissolved in 25 ml of methylene chloride to which 0.14 ml of triethylamine has been added. It cools down

1 4D± 14, -7°C and add 0.1 ml of ethyl chloroformate and then stir for 35 minutes at -5°C. The solution of 0.96 g of cyclopeptide A in 10 ml of methylene chloride added with 0.14 ml of triethylamine is then added. The mixture is stirred for 18 hours under external cooling using an ice bath.

Concentrate to dryness under reduced pressure (25 mm Hg). 0.97 g of impure (N-tertiobutyloxycarbonyl-L-valyl) cyclopeptide A is obtained with a yield of 84%. The product is dissolved in ethyl acetate and the solution is filtered and then washed with water. Concentrate to dryness under reduced pressure (25 mm Hg). One thus obtains 0.73 S of pure (N-tertiobutyloxycarbonyl-L-valyl)-cyclopeptide A in a yield of 63%.

N % = 11.7 (theoretical 12.1)

Rf = 0.70 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume).

Example 4.

2.5 g of L(+) 6-methyl-octanoyl-N-Y-benzyloxycarbonyl-L-a,Y-diaminobutyryl-L-threonyl-N-Y-benzyloxycarbonyl-L-a ,y~ diaminobutyrylhydrazide (prepared according to the method described by K. Vogler et al., Heiv. 48, ll6l (1965)) in 75 ml of glacial acetic acid and 7.08 ml of 1-normal hydrochloric acid. It is cooled to 2°C. 0.232 g of sodium nitrite in 2.5 ml of water is then added to the ice-cooled solution. Stir for 15 min. at 0°C. The solution is poured into a decanting container cooled to 0°C and then 200 ml of a 5% ice-cooled solution of sodium bicarbonate is added. The organic phase is decanted and washed five times successively with 60 ml of 5% ice-cooled bicarbonate solution. The washing water is extracted again with 100 ml of ice-cooled ethyl acetate. The organic extracts are washed with an ice-cooled 5% sodium bicarbonate solution. All organic phases are combined and then dried over anhydrous sodium sulfate at a temperature between 0 and 2°C. One quickly filters and the solution of L(+)-6-methyl-octanoyl-N-Y-benzyloxycarbonyl-L-a,Y-diaminobutyryl-L-threonyl-N-benzyloxycarbonyl-L-a,Y-diaminobutyryl-azide thus obtained is added to an ice-cold solution of 3>23 g of cyclopeptide A in 100 ml of ethyl acetate, with 0.47 ml of triethylamine added. The mixture is stirred for 18 hours at a temperature between 0 and 2°C and for 48 hours at 20°C.

The resulting solution is concentrated to dryness under reduced pressure (25 mm Hg). The residue is dissolved in 100 ml of water. The residue is ground to powder. It is then filtered and dried under reduced pressure (0.3 mm Hg) in the presence of phosphoric anhydride. The product formed is dissolved in 20 ml of acetone, filtered from a small amount of undissolved material and concentrated to dryness under reduced pressure (20 mm Hg).

4.44 g of (L(+)-6-methyloctanoyl-N-Y-benzyloxycarbonyl-L-a,Y-diaminobutyryl-L-threonyl-N-V-benzyloxycarbonyl-L-a,Y-diaminobutyryl) cyclopeptide A is thus obtained in a yield of 79%.

N % = 11.54 (theoretical 11.75)

Rf'= 0.92 (silica gel, 1,2-dichloroethane-methanol, 1:1 parts by volume).

By working in the same way and starting from suitable starting materials, one produces:

(N-α-palmitoyl-N-β-benzyloxycarbonyl-L-lysyl)-cyclopeptide A

N % = lo.51 (theoretical 10.56) C % = 64.65 (theoretical 65.03) H fo = 8.89 (theoretical 9.05)

Rf = 0.75 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume),

(N-α-pelargonyl-N-fc,-benzyloxycarbonyl-L-lysyl)-cyclopeptide A

N f = 11.08 (theoretical 11.32) C % = 63.18 (theoretical 63.55) H % « 8.41 (theoretical 8.66)

Rf = 0.59 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume),

(N-a-palmitoyl-N-X-benzyloxycarbonyl-L-a.Y-diaminobutyryl).-cyclopeptide- A

N % = 10.59 (theoretical 10.76) C % 65.02 (theoretical 64.63) H % = 8.82 (theoretical 8.95)

Rf = 0.68 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume),

(N-oc-L (+)-6-methyloctanoyl-N-Y -benzyloxycarbonyl-L-a,Y -diaminobutyryl)-cyclopeptide A

N f» = 11.13 (theoretical 11.56) C fa = 63.00 (theoretical 63.08) H % = 8.51 (theoretical 8.55)

Rf = 0.55 (silica gel, 1,2-dichloroethane-methanol. 8 : 2 parts by volume).

Example 5.

By working as indicated in example 4 and assuming the following connections:

L( + )-6-methyloctanoyl-N-"f-benzyloxycarbonyl-L-

a,Y -diaminobutyryl-L-threonyl-N-Y-benxyloxy-carbonyl-L-a,Y-diaminobutyrylhydrazide 2.5 g glacial acetic acid 75 ml

l-normal hydrochloric acid 7>08 ml sodium nitrite: 232 mg in solution in 2.5 ml water

(N-methyl-L-valyl)-cyclopeptide A: ^, 6 g in solution in 100 ml of ethyl acetate to which 0.94 ml of triethylamine has been added

5>23 g of (L(+)-6-methyloctanoyl-N-Y-benzyloxycarbonyl-L-a,Y-diaminobutyryl-L-threonyl-N-Y-benzyloxycarbonyl-L-a,f-diaminobutyryl-N-methyl-L-valyl) cyclopeptide is obtained A in a dividend of 87.5%. This product is purified by chromatography on silica gel. 50 g of silica gel is used for 5 g of product and the product is eluted with ethyl acetate and ethyl acetate-methanol

9 : 1 (parts by volume). This purification makes it possible to obtain 2.8 l g of chromatographically pure (L( + )-6-meth<y>loctanoyl-N-Y-benz<y>lox<y>carbon<y>l-L-a,Y-diaminobutyryl-L-threonyl-N-Y -benzyloxycarbonyl-L-α,γ-diaminobutyryl-N-methyl-L-valyl)-cyclopeptide A with a yield of 47

N % 11.79 (theoretical 11.79)

Rf 0.31 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume).

In the same way, the following products are produced:

(N-stearoyl-L-valyl)-cyclopeptide A

N % = 10.46 (theoretical 10.58)-

Rf = 0.45 (silica gel, 1,2-dichloroethane-methanol, 8 : 2 parts by volume)

(N-stearoyl-N-methyl-L-valyl)-cyclopeptide"A

N% ~ 10.02 (theoretical 10.4)

Rf = 0.78 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume).

Example 6.

1.43 6 of heptanoic acid is dissolved in 5 ul of dimethylformamide and then 0.173 g of N-hydroxysuccinimide is added. It cools down

-10°C and adds 0.31 g of dicyclohexylcarbodiimide. Stir for 1 hour. at -10°C, then two hours at 0°C and for 18 hours at 20°C. Formed dicyclohexylurea is eliminated by filtration and the solution of 1.44 g of cyclopeptide A in 75 ml of dimethylformamide to which 0.21 ml of triethylamine has been added is then added to the filtrate. The mixture is stirred for 18 hours at 20°C. The reaction medium is concentrated to dryness under reduced pressure (25 mm Hg). The resulting residue is dissolved in 50 ml of ethyl acetate and washed successively with a 5% aqueous solution of sodium bicarbonate, 1-normal hydrochloric acid and water. The organic phase is dried over anhydrous sodium sulfate. It is then filtered and concentrated

the filtrate to dryness under reduced pressure (25 mm Hg). The residue is chromatographed through 20 times its weight of silica gel, eluting with the chloroform-methanol mixture, successively increasing the methanol content. Heptanoylcyclopeptide A is eluted with a mixture of chloroform-methanol 8:2 (parts by volume). Corresponding fractions are concentrated to dryness under reduced pressure (25 mm Hg).

0.92 g of heptanoyl cyclopeptide A is thus obtained with a yield of 37%.

N % = 11.2 (theoretical 11.77) C % = 62.6 (theoretical 62.83) H % = 8.9 (theoretical 8.94)

Rf = 0.82 (silica gel, 1,2-dichloroethane-methanol, 65:35 parts by volume),

By working in the same way but starting from suitable starting materials, the following products are produced:

stearoyl cyclopeptide A

C % = 65.80 (theoretical 65.70) H % = 9.6 (theoretical 9.62) Rf = 0.82 (silica gel, 1,2-dichloroethane-methanol, 65 : 35 parts by volume),

n-butyryl cyclopeptide A

C lo = 60.9 (theoretical 61.9) H % = 8.7 (theoretical 8.72)

Rf = 0.55 (silica gel, 1,.2-dichloroethane-methanol, 65 : 35 parts by volume),

sorboyl cyclopeptide A

N % = 11.99 (theoretical 11.97)

Rf = 0.75 (silica gel, 1,2-dichloroethane-methanol, 65 : 35 parts by volume),

the hydrochloride of (11-pyrrolidinoundecanoyl)-cyclopeptide A

N % = 10.9 (theoretical 11.35) Cl % = 2.65 (theoretical 2.87) Rf = 0.60 (silica gel, 1,2-dichloroethane-methanol, 65 : 35 parts by volume),

the hydrochloride of (2-pyrrolidinohexanoyl)-cyclopeptide A

N % = ll.8l (theoretical 12.05)

Rf = 0.70 (silica gel, 1,2-dichloroethane-methanol, 65:35 parts by volume).

Example 7.

2.875 g of cyclopeptide A are dissolved in 10.5 ral of dimethylformamide and then 1.28 g of N-tertiobutyloxycarbonyl-L-methionate of 2,4>5-trichlorophenyl are added. The solution is cooled to 0°C, then 0.42 ml of triethylamine is slowly added and then stirred for 18 hours at 0°C. This solution is poured into the mixture of 45 g of ice and 15 ml of cyclohexane to which 0.2 ml of acetic acid has been added. A white oil is obtained which is decanted off and which is dissolved in 6 ml of ethyl acetate. By adding 100 ml of petroleum ether, a white, solid residue is obtained which is filtered off and dried. 2.85 g of (N-tertiobutyloxycarbonyl-L-methionyl) cyclopeptide A is obtained. 1.2 g of this product is dissolved in 2.73 ml of hydrochloric acid dioxane (1.8 N) and kept for 5 hours at 20°C. It is concentrated to dryness under reduced pressure (25 mm Hg), the product formed is dissolved with ethyl acetate and then chromatographed through 15 g of silica gel in a column with a diameter of 1.2 cm. The fractions, eluted with the ethyl acetate-methanol mixture (90 : 10 parts by volume), are combined. The solvent is evaporated under reduced pressure (25 mm Hg), the residue is dissolved with 50 ml of water and the resulting solution is lyophilized. This gives 0.52 g of chlorohydrate of (L-methionyl)-cyclopeptide A .

S % = 2.92 (theoretical 2.84)

Rf - 0.47 (silica gel, 1,2-dichloroethane-methanol, 8 : 2 parts by volume),

By working in the same way but starting from suitable starting materials, you get:

the hydrochloride of (6-pyrrolidinohexanoyl)-cyclopeptide A

N % = 12.05 (theoretical 12.05)

Rf = 0.52 (silica gel, 1,2-dichloroethane-methanol, 65:35 parts by volume).

Example 8.

Dissolve 2 g of cyclopeptide A in 40 ml of methylene chloride and then add 0.28 ml of triethylamine. Cool to a temperature between -5 and -10°C and then add the following two solutions simultaneously within 10 minutes:

a) 0.56 ml of triethylamine dissolved in 15 ml of methylene chloride

b) 0.684 g chlorohydrate of 11-diethylamino-undecyl chloroformate in 15 ml

methylene chloride;

The mixture is stirred for 2 hours at 0°C and then for 18 hours at 20°C. The reaction medium is then washed with a 5 µg solution of sodium bicarbonate and then with a saturated solution of sodium chloride. It is dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (25 mm Hg). The resulting residue is chromatographed through 25 g of silica gel in a column with a diameter of 1.2 cm. The fractions, eluted with mixtures of ethyl acetate-methanol 98:2 and 95:5 (parts by volume), are combined and concentrated to dryness under reduced pressure (25 mm Hg). The residue is dissolved in 40 ml of water and then 1-N hydrochloric acid is added dropwise to pH 3. A small amount of insoluble material is filtered off and the filtrate is lyophilized. 1.24 g of chlorohydrate of (11-diethylamino-undecyloxycarbonyl)-cyclopeptide A is thus obtained with a yield of 50 fo.

N fo = 10.87 (theoretical 11.07)

Rf = 0.64 (silica gel, 1,2-dichloroethane-methanol, 65:35 parts by volume).

In the same way, one produces:

decyloxycarbonyl cyclopeptide A

C % = 63.50 (theoretical 63.08) H % = 9.10 (theoretical 9.08)

N % = 11.95 (theoretical 11.03)

Rf = 0.85 (silica gel, 1,2-dichloroethane-methanol, 8 ■: 2 parts by volume).

Example 9.

2.98 g of cyclopeptide A, 0.569 g of o-nitrophenyl sulfenyl chloride and 0.42 ml of triethylamine are mixed in 40 ml of ethyl acetate at 2°C. The mixture is stirred for 18 hours under external cooling with an ice bath and then concentrated to dryness under reduced pressure (25 mm Hg). 3>45 g of an impure product are obtained, which is chromatographed through 30 g of silica gel in a column with a diameter of 2 cm. The fractions eluted with ethyl acetate are concentrated to dryness under reduced pressure (25 mm Hg). 1 g of (o-nitrophenylsulfenyl)-cyclopeptide A is thus obtained.

N % = 12.1 (theoretical 12.6)

S f 2.85 (theoretical 2.88)

Rf = -0.79 (silica gel, 1,2-dichloroethane-methanol, 8 : 2 parts by volume)..

In the same way, often starting from suitable starting materials, one produces:

(1-dimethylamino-5-naphthalenesulfonyl)-cyclopeptide'A

N fo = 11.66 {theoretical H-.7'5) S % = 2.69 (theoretical 2.69)

-Rf = 0.70 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume), -

p-toluenesulfonyl cyclopeptide A

N % = 11.10 (theoretical 11.33) S ^ 2.56 (theoretical 2.88) Rf = 0.74 {silica gel,' 1,2-dichloroethane-methanol, 8 : 2 parts by volume) ,

p-acetylaminobenzenesulfonyl-cyclopeptide A

N fo = 11.71 (theoretical 12.12) S % 2.93 (theoretical 2.77)

Rf = 0.82 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume).

Example 10.

863 mg of (N-ct-acetyl-N-£-benzyloxycarbonyl-L-lysyl) cyclopeptide A is dissolved in 25 ml of methanol. 863 mg of palladium is added to charcoal (containing 3 f° of active metal). Hydrate with vigorous stirring for 2 hours at 20°C and under a pressure of 760 mm Hg. The solution formed is filtered and the precipitate is washed with 10 ml of 0.5-N hydrochloric acid. The filtrate and the wash water are combined. It is concentrated to dryness under reduced pressure (25 mm Hg) in a rotary evaporator. The residue is dissolved in 5 ml of acetone and the product is precipitated by adding 50 ml of ice-cooled ether. After cooling for three hours at +4 C, the precipitate is filtered off, washed with ether and then dried for 18 hours under reduced pressure (0.3 mm Hg) in the presence of phosphoric acid anhydride. 0.46 g of (N-α-acetyl-L-lysyl)-cyclopeptide A is thus obtained in a yield of 57>6%.

N $ ■= 13.0 (theoretical 13.23)

fa- jl° = "77»2° (° = °>5» methanol)

Rf = 0.56 (silica gel, 1,2-dichloroethane-methanol, 1:1 parts by volume).

In the same way, starting from suitable starting materials, the following products are produced:

the methanesulfonate of L-valyl cyclopeptide A

N %= 11.83 (theoretical 12.14)

Rf = 0.55 (silica gel, 1,2-dichloroethane-methanol, 65 : 35 parts by volume),

the hydrochloride of (L( + )-6-methyloctanoyl-L-oc, f -diaminobutyryl-L-threonyl-L-a,Y -diaminobutyryl)-cyclopeptide A

Cl % = 5.08 (theoretical 4.8l)

Rf ='0.14 (silica gel, 1,2-dichloroethane-methanol, 1:1 parts by volume),

the hydrochloride of (L( + )-6-methyloctanoyl-L-a, y-diaminobutyryl-L-threonyl-L-a}<*>y~diaminobutyryl-R-methyl-L-valyl)-cyclopeptide A

N 1o =13.37 (theoretical 13.25) Cl %■ = 4.47. (theoretical 4>47> Rf = 0.05 (silica gel, 1,2-dichloroethane-methanol, 1 : 1 parts by volume),

(N-α-palmitoyl-L-lysyl)-cyclopeptide A

N % = 10.9 (theoretical 11.3)

Rf = 0.14 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume),

the hydrochloride of (N-α-pelargonyl-L-lysyl)-cyclopeptide A

N % = 12.20 (theoretical 12.19-) Cl % 2.95 (theoretical 2.8l) Rf = 0.08 (silica gel, 1,2-dichloroethane-methanol, 8 : 2 parts by volume),

the hydrochloride of (N-α-Lf + J-G-methyloctanoyl-L-α,^ -diaminobutyryl)-•cyclopeptide A

M % = 12.27 (theoretical 12.48)

Rf = 0.40 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume),

(N-methyl-p-dimethylaminophenyl-DL-alanyl)-cyclopeptide A

H f?= 13.05 (theoretical 13.25)

Rf = 0.5 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume).

Example 11.

0.5 g of (p-methoxybenzyloxycarbonyl-4-amino-cyclohexylcarbonyl)-cyclopeptide A is dissolved in 10 ml of dioxane. 0.25 ml of 4-N anhydrous, hydrochloric acid dioxane is added and the resulting solution is stirred for 18 hours. The solvent is eliminated under reduced pressure (30 mm -Hg) at 35°C and the residue is dissolved with 20 ml of ethyl acetate. The resulting solution is washed with 20 ml of water and decanted from the organic phase, which is evaporated to dryness under reduced pressure (30 mm Hg) at 35°C. The residue is dissolved in 10 ml of dioxane and treated for 4 hours with 0, 84 ml 4_N anhydrous, hydrochloric acid dioxane. The solvent is eliminated under reduced pressure (30 mm Hg) at 35°C and the residue is dissolved in 20 ml of ethyl acetate. The solution is washed with 20 ml of water and the aqueous phase is decanted, which is combined with the aqueous phase formed during the first treatment. Concentrate to dryness under reduced pressure (0.3 mm Hg) at 35<£>>C- Msm dissolve the residue with 10 ml of water, f raf Remove a small amount of insoluble material and evaporate to dryness under reduced pressure, as above . The residue is dissolved in 10 ml of water and lyophilized. 0.355 g of (4-amino-cyclohexylcarbonyl) cyclopeptide A is thus obtained in a yield of 78 g.

N % = 12.75 (theoretical 12.51)

Rf = 0.43 (silica gel, 1,2-dichloroethane-methanol, 8:2 parts by volume).

Example 12.

Dissolve 10 g of cyclopeptide A in 200 ml of methylene chloride and add 1.4 ml of triethylamine. The solution thus formed is cooled to -5°C and the ice-cooled solution of 1.81 g of trichloroacetyl chloride in 20 ml of methylene chloride is then added over the course of 10 minutes. The reaction mixture is stirred for 2 hours at -5°C and then for 18 hours at room temperature. The solvent is eliminated by distillation under reduced pressure (30 mm Hg) at 50°C and the residue is dissolved in 100 ml of ethyl acetate. Insoluble material is eliminated by filtration and the filtrate is washed successively with twice 75 ml of a 5# ice-cooled solution of sodium bicarbonate with twice 75 ml of 1-n hydrochloric acid and then with 30 ml of a saturated solution of sodium chloride. The organic phase is dried over sodium sulphate, filtered and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg) at 50°C. 7.23 g of impure product is thus obtained, which is dissolved in 20 ml of ethyl acetate and which is passed through a column with a diameter of 2 cm and containing 125 g of silica gel. Elution is carried out using ethyl acetate. The product is collected in fractions between 150 and 450 ml of eluate after elimination of the solvent under reduced pressure (30 mm Hg) at 50°C.

After drying at 30°C under reduced pressure (0.1 mm Hg), 6 g of trichloroacetyl cyclopeptide A are obtained in a yield of 53$•

N % = 10.9 (theoretical 11.13)

Rf =0.8 (silica gel, 1,2-dichloroethane-methanol, 65 : 35

volume fractions).

Example 13.

Dissolve 65 g of N-lauryl-N-methyl-D-valine in 800 ml of methylene chloride and add 51 ml of triethylamine. After cooling the reaction medium in an ice bath, 182 g of cyclopeptide A and then 42.5 g of dicyclohexylcarbodiimide are added. The mixture is stirred for 18 hours at 2°C and then 48 hours at a temperature close to 20°C. 5 ml of glacial acetic acid are then added, after which the formed precipitate is filtered. Concentrate to dryness under reduced pressure

(25 mm Hg) and dissolve the residue in 500 ml of ethyl acetate. The resulting suspension is poured into an ice bath for 30 min., after which it is filtered from insoluble material. The filtrate is concentrated to dryness under reduced pressure (25 mm Hg).

The impure product thus formed is purified by chromatography. For this purpose, the solution of the impure product in 500 ml of ethyl acetate is poured through a column with a diameter of 10 cm containing 2 kg of silica. The elution is carried out using mixtures of ethyl acetate/methanol with an increasing content of methanol. Fractions of 300 ml are collected. The fractions eluted with the mixtures ethyl acetate/methanol (98:2 parts by volume) are combined and then concentrated to dryness under reduced pressure (25 mm Hg). The product formed is dissolved in 900 ml of water. It is acidified to pH 1 by adding 1-n hydrochloric acid, after which it is stirred for 2 hours until complete dissolution. Concentrate to dryness under reduced pressure (0.3 mm Hg) to drive off excess hydrochloric acid, after which the residue is dissolved in 500 ml of water and concentrated to dryness under reduced pressure (0.3 mm Hg). The residue is dissolved in 900 ml of water and lyophilized.

74 g of chlorohydrate of N-lauryl-N-methyl-D-valyl-cyclopeptide A is thus obtained.

G % - 62.7 (theoretical 63.06)

H % = 9.25 (theoretical 9.25)

Cl% = 2.6 (theoretical 2.77)

Rf = 0.51 (silica gel 1,2-dichloroethane-methanol, 8:2 parts by volume). Example 14.

Work as in example 13, but use 1.75 g

N-undecyl-N-methyl-D-valine in 110 ml of methylene chloride, 1.52 ml of triethylamine, 5.4 g of cyclopeptide A and 1.12 g of dicyclohexylcarbodiimide. After chromatography through a column containing 120 g of silica, 1.83 g of N-undecyl-N-methyl-D-valyl cyclopeptide A is obtained.

C% = 64.0 (theoretical 64.68)

H% = 9j09 (theoretical 9.54)

N% = 11.1 (theoretical 11.43)

Rf - 0.63 (silica gel: 1,2-dichloroethane-methanol, 8:2 parts by volume). Example 15.

One works as in example 13, but uses 4.8 g of N-myristyl-N-methyl-D-valine in 27 ml of methylene chloride, 2.4 ml of triethylamine, 10.3 g of cyclopeptide A and 2.09 g of dicyclohexylcarbodiimide. After purification of the impure products by chromatography through a column containing 100 g of silica and then conversion to chloral hydrate, 2 g of chloral hydrate of N-myristyl-N-methyl-D-valyl-cyclopeptide A is obtained.

N% - 10.5 (theoretical 10.73)

Z\ t- 2.56 (theoretical 2.71)

Rf = 0.68 (silica gel: 1,.2-dichloroethane-methanol, 8:2 parts by volume).

Example 16.

One works as in example 13, but uses 1.4 g of N-tricedyl-N-methyl-D-valine in 80 ml of ethyl acetate, 1.12 ml of triethylamine, 4 g of cyclopeptide A and 0.9 g of dicyclohexylcarbodiimide.. After purification of the impure product by chromatography through a column containing 50 g of silica and then conversion to chloral hydrate yields 0.48 g of chloral hydrate of N-tridecyl-N-methyl-D-valyl-cyclopeptide A.

N# = 10.32 ("theoretical 10.85)

Cl% - 2.77 (theoretical 2.82).

Rf = 0.75 (silica gel: 1,2-dichloroethane-methanol, 8:2 v/v).

Claims (1)

Analogous process for the production of new, therapeutically effective cyclopeptides with the general formula R' - cyclopeptide A (I) where - cyclopeptide A denotes a nonapeptide residue of the formula and R' denotes an alkanoyl-, alkenoyl-,. alkadienoyl, alkyloxycarbonyl, aralkanoyl, aroyl, arylsulfenyl, arylsulfonyl, cycloalkylcarbonyl, heterocyclylcarbonyl or heterocyclylalkanoyl group or a residue of a linear peptide group which is connected through a carbonyl group at the nitrogen atom of the L-4-transmethylproline in the side chain of the cyclopeptide A, the alkyl parts in the alkanoyl groups are straight or branched chains containing 1-17 carbon atoms, possibly substituted with one or more halogen atoms, amino groups or methylthio groups, the alkenyl parts in the alkenoyl groups contain 10 carbon atoms, the alkadienyl parts in the alkadienoyl groups contain 5 carbon atoms, the alkyl parts in the heterocyclylalkanoyl groups are straight or branched chains containing 2-10 carbon atoms, the alkyl parts in the alkyloxycarbonyl groups containing 9-11 carbon atoms and optionally substituted with a diethylamino group, the alkyl parts in the aralkanoyl groups containing 1 or 2 carbon atoms and optionally substituted with an amino group, the aromatic parts in aralkanoyl-, aroyl-, the arylsulfonyl or arylsulfonyl groups are made up of a benzene or naphthalene nucleus, which is optionally substituted with a methyl, hydroxyl, dimethylamino, acetylamino, nitro, benzoyl or diethylamino group, the heterocyclic parts in the heterocyclylcarbonyl or heterocyclylalkanoyl groups being 5- or 6-membered mononuclear heterocycles containing nitrogen or a phenotiazinyl group which may be substituted with one or more methyl or nitro groups, the cycloalkyl part of the cycloalkylcarbonyl groups forming a cyclohexyl group substituted with an amino group, the residues of the linear peptide groups containing 2-3 amino acids of series L, and since the amino groups which constitute substituents on the alkyl or cycloalkyl parts in the groups defined above, as well as the amino groups of the linear peptide groups can possibly be substituted with one or more straight-line or branched alkyl groups, containing .1 - 14 carbon atoms, alkanoyl groups containing 2-18 carbon atoms, tert.butyloxycarbonyl, benzyl or benzyloxycarbonyl groups, in the form of bases, addition salts with acids and quaternary ammonium salts, characterized by a) condensing H-cyclopeptide A with an acid -with the general formula R'OH, where R' denotes a alkanoyl, alkenoyl, alkadienoyl, aralkanoyl, aroyl, cycloalkylcarbonyl, heterocyclylcarbonyl or heterocyclylalkanoyl group or a residue of a linear peptide group, these various groups may have the above definitions, and the amino groups present are substituted as indicated above, or with an activated derivative of this acid such as an azide, an activated ester, an acid anhydride or an acid chloride, or b) when R' denotes an alkyloxycarbonyl group which is optionally substituted in the above-mentioned manner, one reacts an alkyl chloroformate which is optionally substituted in the above-mentioned manner with H-cyclopeptide A, or c) when R' denotes an arylsulfonyl or arylsulfonyl group, reacts a compound of the general formula where RIV is a benzene or naphthalene nucleus, which is optionally substituted as indicated above, and n is 0 or 2, with H-cyclopeptide A, after which one optionally converts a thus formed compound of formula where -cyclopeptide A has the above meaning, and R« and which may be the same or different, denotes a hydrogen atom or an alkyl group, containing 1 to 5 carbon atoms, into another compound of formula (I ) by reaction with an acid of the general formula R'OH, where R' denotes an alkanoyl group, containing 2-18 carbon atoms or a linear peptide residue, containing 1-2 amino acids, whose amino groups can be substituted in the above-mentioned manner, or with an activated derivative of this acid as an azide, an activated ester, an acid anhydride or an acid chloride, after which, through acid hydrolysis or catalytic hydrogenation, the amino groups which are substituted with tert-butyloxycarbonyl, benzyl or benzyloxycarbonyl groups are optionally released and the base formed is converted into a salt' or vice versa.